The overall objective of this research is to identify putative drug treatments in the pre-clinical setting that can rapidly translate into post-withdrawal pharmacotherapy for methamphetamine (METH) addiction. Methamphetamine is an increasingly popular psychostimulant/hallucinogenic drug with an extremely high abuse liability. Presently, there is no cure for METH addiction. Indeed, the overwhelming majority (up to 85%) of patients undergoing modern day drug rehabilitation relapse back into compulsive drug taking. In rats, repeated injections of METH induce behavioral sensitization, and the brain adaptations that accompany this behavior are thought to emulate those that occur in the METH addict. By evaluating processes that endure long after METH withdrawal, Wolf and Napier's laboratories have identified a pattern of biochemical and electrophysiological changes that occur in the brain following METH-induced behavioral sensitization. Their preliminary data also have revealed that post-withdrawal administration of the 5-HT2A/2C antagonist, mianserin, reversed the sensitized behaviors established by METH. These findings directed the hypotheses that 1) increases in 5-HT2A/2C function contribute to METH-induced sensitization, and 2) 5-HT2A/2C antagonists can reverse behavioral sensitization and its associated neuroadaptive changes when the antagonists are administered after sensitized responding has developed. For the present SBIR, we pose to evaluate the efficacy of known 5-HT2 antagonists with differing pharmacological profiles to reverse METH-induced sensitization. The drugs are mianserin, the structurally related drug, mirtazapine and the structurally un-related drug ketanserin. The following aims are proposed: Specific Aim I. Using a post-sensitization test paradigm, our pilot behavioral study with mianserin will be replicated and the ability mirtazapine and ketanserin to reverse METH-induced behavioral sensitization will be ascertained in rats. These will direct the experiments in Aim II. Specific Aim II. In METH-sensitized rats, 5-HT2-mediated transcription factors (activated CREB and deltaFos B) will be determined in brain regions known to be involved in addictive behaviors. The ability of the 5-HT2 antagonist identified in Aim 1 to reverse these effects will be ascertained. Those regions showing an antagonist-induced reversal of METH-induced effects in biochemical markers will then be evaluated for its ability to reverse electrophysiological measures of neuronal function. This distinctive post-sensitization test paradigm will help reveal the therapeutic potential of test compounds for relapse prevention. These studies also will help identify drug treatment that can be rapidly translated into anti-addiction medication for the METH addict. The phase II SBIR goals will be to establish additional or novel drug candidates for METH addiction therapy through internal Solentix drug discovery efforts. The results of this research will be utilized to explore additional biological screens for other drugs of abuse and subsequent identification of novel therapies.